EP1480979B1 - Oligomere der gadolinium chelate, ihre verwendung als nmr-kontrastmittel und zwischenverbindungen - Google Patents

Oligomere der gadolinium chelate, ihre verwendung als nmr-kontrastmittel und zwischenverbindungen Download PDF

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EP1480979B1
EP1480979B1 EP03727569A EP03727569A EP1480979B1 EP 1480979 B1 EP1480979 B1 EP 1480979B1 EP 03727569 A EP03727569 A EP 03727569A EP 03727569 A EP03727569 A EP 03727569A EP 1480979 B1 EP1480979 B1 EP 1480979B1
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formula
conq
compounds
alkyl
groups
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EP1480979A2 (de
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Isabelle Nachman
Marc Port
Isabelle Raynal
Olivier Rousseaux
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Guerbet SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A61K49/124—Macromolecular compounds dendrimers, dendrons, hyperbranched compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/65812—Cyclic phosphazenes [P=N-]n, n>=3
    • C07F9/65815—Cyclic phosphazenes [P=N-]n, n>=3 n = 3

Definitions

  • the present invention relates to oligomers of paramagnetic chelates, their application as vascular remanence contrast media for magnetic resonance imaging (MRI) as well as their preparation methods and synthesis intermediates.
  • MRI magnetic resonance imaging
  • the administration of contrast agents to patients helps to improve the resolution of the images obtained and the accuracy of the diagnosis.
  • the longitudinal relaxivity r 1 of a paramagnetic contrast product gives the measurement of its magnetic efficiency and makes it possible to appreciate its influence on the recorded signal;
  • the mass efficiency defined as the ratio of r 1 to the molecular weight of the compound gives, for its part, the measure of the effectiveness of the weight unit of the contrast product and makes it possible to compare the products in terms of weight administered diagnostic dose including tolerance and cost.
  • Gadolinium chelates used in human clinics, such as Magnevist ® , Dotarem ® or Omniscan ® , are of low molecular weight, have relaxivities r 1 less than 5 mM -1 s -1 and are distributed rapidly in the extravascular space after their injection.
  • BPAs Blood Pool Agents
  • vascular remanence limits the elimination of contrast material by the kidneys and transfer to extravascular compartments.
  • BPAs aim to improve characterization of lesions (eg vascularization of lesions or detection of bleeding) and organ perfusion, including myocardial perfusion.
  • RC BPA Rapid Clearance Blood Pool Agents
  • the level of vascular remanence of these RC BPA products makes them advantageous in preferred applications such as myocardial perfusion or coronary angiography where they can be used in several injections successively.
  • RC PBA products described in the document EP 922 700
  • products of the dendrimer type several gadolinium chelates are grafted on the periphery of a tree structure "full and dense" with a large footprint forming a kind of solid sphere (Gadomer17® for example).
  • SC BPA Small Clearance Blood Pool Agent
  • New BPAs whose vascular persistence is greater than that of known BPA RC, aim at significant improvements, in particular, in the determination of the blood volume in the different tissues, the differentiation of cancerous tumors, the identification of inflammatory zones or lymphography. .
  • These new oligomers comprise several functionalized gadolinium chelates which have been grafted on a molecule, the central nucleus, bearing groups capable of reacting with these coupling functions.
  • the coupling functions are amine functions.
  • these oligomers are obtained from monomers of chelates, these polymetals carry 3 to 6 gadolinium chelates.
  • these oligomers are obtained from chelate dimers; these polymetallics typically carry from 4 to 8 gadolinium chelates.
  • the molar mass efficiency (em) in g -1 s -1 is the ratio: (number of Gd x r1 ⁇ 1000) / molecular weight of the molecule).
  • the new products obtained have greater Gd relaxivities, a higher Gd mass efficiency (the mass efficiency of the polymetallic oligomer is greater than that of the corresponding monometallic monomer), a monodispersity and purity controlled.
  • the structure of the RR chelates previously described had to be modified to introduce a group capable of reacting on the precursor molecule of the central nucleus, without this modification leading to a loss of stability or magnetic efficiency.
  • the invention relates to polymetallic molecules, of the following general formula: CENTRAL CORE - link 2 - div o - ( link 1 - Gd heart - ( plugged ⁇ ) not ) s m
  • the Gd hearts have been chosen from:
  • the inventors have also studied compounds using restricted rotation Gd cores of the DTPA type described in particular in document EP 661 279, of general formula: with R1, U as described below.
  • Such hydrophilic branches forming lateral arms on the acidic groups may be of different nature and are intended to reduce the freedom of movement of the paramagnetic complex and the paramagnetic ion attached to it, the rotation of which in the magnetic field (function inverse of r1) is thus restricted.
  • divisors are possible, as long as they make it possible to make the connection (preserving the star structure) between on the one hand at least two chelates, and on the other hand a polyfunctional central core .
  • Different polyfunctional backbones can be used by those skilled in the art as divisors, described in Chemical Reviews, 2001, 101 (12), 3819-386 and Topics in Current Chemistry, Vol. 217, 2212, 210, 197.
  • Preferred divisors are polyfunctionalized aromatic skeletons with carboxylate and / or amino groups.
  • the invention also relates to the salts of the compounds of formula (E) with acids or inorganic or organic bases, in particular the hydrochlorides of the amino groups and the sodium, potassium and N-methylglucamine salts of the carboxylic acid groups present on the chelates.
  • the invention also relates to the salts of the compounds of formula 11 with acids or inorganic or organic bases, in particular the hydrochlorides of the amino groups and the sodium, potassium and N-methylglucamine salts of the carboxylic acid groups present on the chelates.
  • a criterion of choice may be the chemical accessibility to the starting polyacid and / or its reactivity with the derivatives of the chelates carrying an amine function.
  • the polyacids are known products or they can be prepared by conventional methods of etherification, carboxylation, amidification from known products.
  • the compounds of formulas II '2 II "a2, II” b2 are obtained from two equivalents of the compounds of structure V 1 as defined in the application, by double substitution reaction of 2,4,6-trichloro- 1,3,5-triazine in an aqueous medium or in a mixture of water and a polar solvent miscible with water, controlling pH and temperature.
  • residues of formula R- are introduced by peptide coupling according to the methods known to those skilled in the art, corresponding amines of formula R-NH 2 , the structure of which has been defined previously, for example in an aqueous medium in the presence of an agent compatible coupling such as EDCI and possibly a catalyst.
  • the compounds of formula II "' 2 are prepared starting from the amine precursors derived from the residues of formula II"' 1 and of structure: according to an analogous protocol by double substitution of the triazine ring and displacement of the residual chlorine atom by a large excess of diamine as defined above.
  • the compounds of formula I1 or I2 in which Q 1 represents CH 2 CHOHCH 2 OH or CH 2 (CHOH) 4 CH 2 OH and Q 2 represents CH 2 (CHOH) 4 CH 2 OH, especially in the CONQ 1 Q 2 groups. are generally preferred for forming sufficiently hydrophilic molecules in terms of aqueous solubility and biocompatibility.
  • the products of formula I1 can be prepared either from amines A1H or from one of their precursors A'1NH, especially the compounds in which there is (CH 2 ) x COOH instead of (CH 2 ) x CONHR in B 1 , B 2 or B 3 .
  • A1H and A'1NH, functionalized derivatives of macrocyclic gadolinium chelates are synthesis intermediates of all the novel compounds of formula I1, which it was necessary to develop a preparation method adapted to the nature of amino acid of the reactive group grafted onto the macrocycle making it possible to fix the chelate on the remainder W1 without loss of stability of the macrocyclic chelate.
  • the invention therefore also relates to the precursors of the polymetallic compounds according to the invention, necessary for their synthesis.
  • the precursor V1, VI1 or VI'1 is preferably reacted with 2,4,6-trichloro-1,3,5-triazine under the conditions
  • the reaction can be carried out in the presence of a mineral base such as NaOH or Na 2 CO 3 or a tertiary amine, such as triethylamine, for example in water in the presence of 5 to 60% by volume of dioxane.
  • a mineral base such as NaOH or Na 2 CO 3
  • a tertiary amine such as triethylamine
  • the chelates V1 or VI1 or optionally the condensation product on W1 carry the acid groups: and can then be reacted with the amine RNH 2 in an aqueous medium, optionally in the presence of a third solvent such as dioxane or tetrahydrofuran, with activation of the carboxylic groups by addition of a soluble carbodiimide, which carries a amine group as described in J. Org.
  • N-hydroxysulfosuccinimide (NHS), Bioconjugate Chem. 5, 1994, 565-576 or 2-succinimido-1,1,3,3-tetra-methyluronium tetrafluoroborate Tetrahedron Letters, 30, 1989, 1927-1930.
  • a mixture of EDCI and NHS can also be used.
  • W1 is a polyacid derivative
  • the gadolinium complex is then prepared according to one of the known methods, in particular US Pat. No. 5,554,748 or Helv. Chim. Acta, 69, 1986, 2067-2074, by the action of Gd 2 O 3 or GdCl 3 in an aqueous medium at a pH of between 5 and 7.
  • the invention also relates to contrast products for medical magnetic resonance imaging which comprise at least one compound of formula (E), preferably of formula Poly M RR and Poly D RR, optionally combined with a vehicle and with additives pharmaceutically acceptable for oral administration or subcutaneous, or percutaneous, intravascular injection.
  • Diagnostic compositions for the oral route will be presented in the form of tablets or capsules, or suspensions and oral solutions.
  • the aqueous solubility and the low osmolality of the compounds of the invention make it possible to prepare isotonic aqueous solutions of high concentration and acceptable viscosity for injection.
  • the invention in another aspect, relates to paramagnetic complexes formed between ligands of the invention and suitable paramagnetic metal ions, other than gadolinium, such as those of dysprosium or manganese, as well as contrast agent compositions. for medical magnetic resonance imaging which include these complexes, associated with the usual vehicles and additives.
  • the ligands according to the invention can also form complexes with radioelements such as Tc, In, or Yb, which can be used to establish a diagnosis or to perform a therapeutic treatment.
  • These complexes are, in general, in the form of internal salt, resulting from the neutralization by the central metal cation of acid groups of the ligand; when the complex comprises other acid groups these may be salified with a pharmaceutically acceptable inorganic or organic base including amino acids, for example NaOH, lysine, N-methylglucamine, arginine, ornithine or diethanolamine.
  • a pharmaceutically acceptable inorganic or organic base including amino acids, for example NaOH, lysine, N-methylglucamine, arginine, ornithine or diethanolamine.
  • the doses at which the contrast agents according to the invention can be administered depend on the nature of the complex, the relaxivity it induces, the route of administration and the target organ. For example, orally, in particular for the gastrointestinal sphere, it will be possible to administer on the order of 0.01 to 3 mmol / kg of animal, and parenterally of the order of 0.001 to 0.02 mmol / kg.
  • additives may be introduced into the diagnostic compositions of the invention such as buffers, antioxidants, electrolytes, surfactants, polyols, as well as other chelates of biological cations or complexing agents in small amounts.
  • the solutions can be prepared extemporaneously from the lyophilized powder containing the compound of formula (E) and optionally additives and a sterile solvent or, because of the high stability of the complexes in solution in vitro, such as in vivo, the solutions can be provided to the radiologist in vials or syringes.
  • the unit doses will depend on the structure of the compound of formula E, the route of administration, the type of diagnosis to be established, as well as the patient.
  • the unit doses will generally be from 0.1 ⁇ mol to 150 ⁇ mol of gadolinium per kg, preferably from 1 to 100 ⁇ mol of gadolinium per kg for a man of average size.
  • the diagnostic compositions of the invention are useful for imaging blood vessels and lymphoid tissues. They allow the determination of perfusion and blood volume in pathological territories, the study of microvascular permeability and the identification of ischemic states or the characterization of tumors and inflammatory conditions.
  • the invention therefore relates in particular to the use of diagnostic compounds of formula (E) and in particular of formula I1 or 12, for imaging diagnosis, and their use for the preparation of a composition for the diagnosis of these indications.
  • the invention also relates to a medical imaging diagnostic method using these compounds.
  • Examples 1 to 13 and 39 relate to polymetallic monomers.
  • Examples 25 to 36, 38, 41 and 43 relate to polymetallic dimers; Examples 14 to 24, 37, 40 and 42 of the dimeric precursors of these polymetals.
  • Pentadeca-1 15
  • 11,13-triene are introduced into 440 ml of CH 3 CN in the presence of 48 g of K 2 CO 3 calcined and the mixture is maintained at 80 ° C for 1 h before the addition of a solution of 93 g of ethyl 2-bromoglutarate in 100 ml of CH 3 CN; the reaction medium is then stirred for 20 h at 80 ° C and then cooled to room temperature, filtered and the solvent is evaporated.
  • the aqueous phase is washed with 1 volume of diethyl ether and then toluene before being brought to pH 6 by addition of NaOH (1N).
  • reaction medium After filtration, the reaction medium is evaporated and the residue is crystallized from ethanol.
  • the residue is taken up in diethyl ether and the suspension is filtered. After removal of the solvent, the residue is introduced in portions into a slurry of minus 5 ml of weak anionic resin (OH - ) in 50 ml of water; at the end of the addition the pH, stable, must be 8 to 8.5.
  • weak anionic resin OH -
  • the resin is then separated by filtration, the solvent removed and the residue precipitated by the addition of ethyl ether.
  • reaction medium is taken up in CH 2 Cl 2 and the organic phase is washed with H 2 O and then dried over magnesium sulfate. After evaporation of the solvent, 37.5 g of crystals are obtained which are engaged in the next step.
  • reaction medium After stirring for 3 h at 25 ° C., the reaction medium is evaporated to dryness and the residue is taken up in 400 ml of CH 2 Cl 2 . The organic phase is washed twice with 100 ml of H 2 O.
  • the red-colored reaction medium is stirred for 6 h at 25 ° C. and then 400 ml of H 2 O and 400 ml of CH 2 Cl 2 are added thereto. After stirring and decantation, the aqueous phase is separated and extracted with 400 ml of CH 2 Cl 2 . This organic phase, after washing twice with water, is combined with the previous phase and the whole is concentrated. The oily residue is purified by flash chromatography on silica (Merck®, 40-63 ⁇ m), eluting with a CH 3 OH / NH 4 OH mixture (50/1) after removal of the impurities by elution with CH 3 OH.
  • step d) To a solution of 8 g of compound obtained in step d) in 60 ml of CH 3 CN and 26 ml of diisopropyl ether, 22 g of ethyl 2-bromoglutarate and 11 g of calcined K 2 CO 3 are added. then the mixture is brought to its reflux temperature for 24 hours.
  • the oil obtained is purified by flash chromatography on silica (Merck ®, 40-63 .mu.m) eluting with heptane / ethyl acetate (60/40 v / v).
  • the oil obtained is purified by flash chromatography on silica (Merck ®, 40-60 .mu.m) eluting with a mixture of CH 2 Cl 2 / CH 3 OH (97/3, v / v ).
  • the pH of the suspension is brought to 5 by addition of a 2N aqueous NaOH solution and then the medium is heated at 50 ° C. until complete solubilization.
  • the oil obtained is purified by chromatography on silica (Merck® 40-63 ⁇ m) eluting with a CH 2 Cl 2 / acetone mixture (70/30 v / v).
  • step d) of Example 2 By applying the same procedure as for step j) of Example 2, 4 g of product are obtained from 4.5 g of the compound obtained in step d).
  • a suspension containing 20 g of the compound obtained in step a) and 20 g of Na 2 CO 3 in 400 ml of CH 3 CN is brought to reflux temperature for 15 min before adding 40 g of 2-bromoglutarate dropwise. of methyl.
  • the medium is heated at 80 ° C. for 2 hours during which the pH is maintained between 5.2 and 5.5 by the addition of an aqueous solution of 6M HCl.
  • a solution consisting of 109 g of benzyl 2-bromo glutarate in 200 ml of dry CH 3 CN is rapidly added to a suspension of 45 g of the compound obtained in step a) in 500 ml of CH 3 CN, previously heated to 80 ° C.
  • a solution of 5 g of the crude product obtained in step b) in 25 ml of 2N aqueous HCl solution is refluxed 24 hours. After cooling, 100 ml of water are added before extracting the aqueous phase with three times 50 ml of diethyl ether.
  • a) 16 g of the compound obtained in step e) of Example 1 and 61 g of the amine RNH 2 are dissolved in 600 ml of H 2 O.
  • the solution is brought to pH 6 by adding a aqueous solution of 1N NaOH and then 20 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (EDCI) and 1.1 g of N-hydroxysulfosuccinimide acid (NHS) are added.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride
  • NHS N-hydroxysulfosuccinimide acid
  • the product obtained by filtration is then purified by chromatography on a silanized silica column, eluting with H 2 O and then with H 2 O / CH 3 OH mixtures.
  • the residue is crystallized from diethyl ether.
  • the product obtained is added in portions to 10 ml of anionic resin OH - (Amberlite ® IRA67) in 100 ml of water, always maintaining the pH of the solution above 5 during the addition by adding possible resin.
  • the solution whose pH is stabilized around 8 is filtered to remove the resin and then evaporated. After drying, 20 g of white crystals are obtained.
  • the solution is poured into 100 ml of C 2 H 5 OH and the precipitate obtained is filtered off and then redissolved in 40 ml of water.
  • the solution is ultrafiltered on a polyether sulfone membrane (Pall ® ) with a cut-off threshold of 5 KD and then on a membrane with a cutoff threshold of 10 KD. After evaporation of the water, 10 g of crystals are obtained.
  • A1 represents the same group as that of Example 7.
  • the reaction medium is stirred for 4 days during which the pH is regularly brought to 8.4 by addition of a 0.2M aqueous solution of NaOH.
  • the precipitate obtained is redissolved in 100 ml of water to be purified by ultrafiltration on a polyether sulfone membrane (Pall®) with a cut-off of 10 KD.
  • Pall® polyether sulfone membrane
  • the retentate is concentrated and purified by chromatography on a silanized silica column (Merck®) (diameter: 7 cm, height: 33 cm) eluting with water and then water / methanol mixtures (90/10 V / V at 80 ° C.). / 20). Fractions containing the desired product are concentrated until the solvents are removed.
  • 131 mg of hexaacid derived from cyclotriphosphazene, already used in example 9, are introduced into 55 ml of dimethylsulfoxide with 4.4 g of the solid obtained in step a) and 0.42 mg of triethylamine, then 350 mg of EDCI and 250 mg of HOBT.
  • the solution is introduced into 300 ml of ethanol; the precipitate then formed is dissolved in 200 ml of water and the ultrafiltered solution on a polyethersulfone membrane with a cut-off of 10 kD.
  • the residue is treated in 50 ml of water successively with an anionic resin in OH - then cationic form, before removing the water.
  • 2,4,6-trichloro-1,3,5-triazine cyanuril chloride
  • 0.5 g of the compound of step e) of Example 3 are added to 2.5 ml of water.
  • the product is solubilized by bringing the pH of the solution to 7 by adding a sodium hydroxide solution (0.1 N).
  • the reaction medium is heated to 60 ° C. and a homogeneous solution formed by 0.029 g of 2,4,6-trichloro-1,3,5-triazine in 1 ml of dioxane is added all at once.
  • the compound MC611, called type P730 (the core Gd is a DOTA type core with substituted alpha carbon) with branch AAG1 AA28 Br has the following formula:
  • the MC 723 compound has the formula:
  • Table 3 Effectiveness of polymetallic compounds of dimers (at the 0.47 T, 20 MHz field) monometallic reference compound dimeric polymetallic compound tested example number Family molecular weight Number of Gd relaxivity r1 by Gd (mM -1 .Gd.s -1 ) r1 / mole (mM -1 s -1 ) Molar mass efficiency em (g -1 s -1 ) Gd rate (%) Plugged P 855 15 P730 17292 4 35.1 140 8.1 3.64 AAG1AA28 Br P 856 16 P730 17381 4 34.8 139 8 3.62 AAG1AA28 Br P 858 17 P730 26068 6 39.9 239 9.2 3.62 AAG1AA28 Br P 865 18 P730 34850 8 37.9
  • the data were measured at a frequency of 20 MHz which is a common frequency for the diagnostic indications concerned.
  • Favorable results have also been obtained at higher frequencies, for example 40 MHz.
  • the compounds according to the invention are very useful in diagnostic imaging, especially in the characterization of tumors. Conclusive tests have been obtained for example on human mammary tumors and in the rat.
  • the inventors obtained, in particular, the following results.
  • the controls were Dota-dysprosium, and the compound P792 (described in the patent issued EP 922 700) which is a monometallic product based on Gd whose pharmacokinetic profile is that of a RCBPA.
  • the measurements will be performed 30 and 60 minutes post-injection.
  • ENU carcinogen doses of 45 mg / kg, mainly to induce fibroadenomas (benign tumors) and 180 mg / kg, to induce predominantly adenocarcinomas (malignant tumors) were tested.
  • concentrations of contrast medium measured in adenocarcinomas are markedly superior to those recorded in muscle (tumor / muscle enhancement) and those obtained in fibroadenomas (malignant tumor / benign tumor enhancement).
  • the ratio of tumor / muscle concentrations is close to 4.
  • the ratios are different: the ratio is 4 to 5 for fibroadenomas versus 8 to 9 for adenocarcinomas, which makes it possible to differentiate between benign and malignant tumors, 1 hour after injection.
  • Daldrup-Link and colleagues have shown that Gadomer-17 does not allow such differentiation in MRI in this model [Daldrup-Link HE et al. Of gadomer-17 and gadopentetate dimeglumine for differentiation of benign from malignant breast tumors with MR imaging. Acad.
  • Gadomer-17 a new dendritic magnetic resonance contrast agent. MAGMA. 2001. 12: 128-134.]. Therefore, despite a comparable molecular weight, Gadomer-17 has rather a pharmacokinetic behavior that is not suitable for highlighting differences in vascular permeability between the two types of tumors, unlike polymetallic compounds according to US Pat. 'invention. Polymetallics obtained by the inventors allow, at the time chosen, not only a significant tumor enhancement of the signal relative to the muscle, but also to differentiate the tumors, the concentrations contained in the adenocarcinomas being significantly higher than those found in fibroadenomas.

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Claims (31)

  1. Verbindungen der folgenden allgemeinen Formel:

            W-(A)m     (E)

    worin:
    - W ein zentraler KERN ist,
    - A [(D)q-(Ia,b,c,d,e,f)r] darstellt
    und
    - q = 0 oder q = 1,
    - r = 1, wenn q = 0 oder r 2 oder 3 ist, wenn q = 1,
    - m zwischen 3 und 6 ist, wenn q = 0 und m zwischen 2 und 4 ist, wenn q = 1,
    - D ein polyfunktionelles Molekül ist, das über eine Verbindungsgruppe 2 an den zentralen KERN W und über Verbindungsgruppen 1 an wenigstens zwei Metallchelate binden kann,
    - Ia,b,c,d,e,f Ia oder Ib oder Ic oder Id oder Ie oder If bedeutet und Derivate mit eingeschränkter Rotation darstellt,
    wobei Ia, Ib, Ic die Bedeutungen:
    Figure imgb0292
     aufweisen, worin:
    - X CO2R'a, CONR'bR'c oder P(R'd)O2H darstellt und
    R'a, R'b, R'c H oder gegebenenfalls hydroxyliertes (C1-C8)Alkyl darstellen;
    R'd OH, (C1-C8)Alkyl oder (C1-C8)Alkoxy, (C1-C8)Arylalkyl oder (C1-C8)-Alkoxyalkyl darstellt,
    - R1 eine hydrophile Gruppe mit einer Molmasse über 300 und unter 3000 darstellt, die mindestens drei Sauerstoffatome umfaßt und aus den folgenden Gruppen ausgewählt ist:
    - Polyoxy(C2-C3)alkylen, insbesondere Polyethylenglykol und seine C1- bis C3-Monoether und Monoester
    - Polyhydroxyalkyl
    - Polyol
    - (R2g)e[(R2g)iR3]h, worin:
    - h = 1 oder 2, i = 0, 1 oder 2, e = 1 bis 5
    - R2 (wobei R2 gleich oder verschieden ist)
    - fehlt oder ein Alkylen, ein Alkoxyalkylen, ein Polyalkoxyalkylen;
    - ein Phenylen oder einen gesättigten oder ungesättigten heterocyclischen Rest darstellt, der gegebenenfalls durch OH, Cl, Br, I, (C1-C8)Alkyl, (C1-C8)Alkyloxy, N02, NRxRy, NRxCORy, CONRxRy oder COORx substituiert ist, wobei Rx und Ry H oder (C1-C8)Alkyl sind und die geraden, verzweigten oder cyclischen C1- bis C14-Alkyl-, Alkylen- und Alkoxygruppen hydroxyliert sein können,
    - g (wobei g gleich oder verschieden ist): fehlt oder eine Funktion O, CO, OCO, COO, SO3, OSO2, CONR', NR'CO, NR'COO, OCONR',NR', NR'CS, CSNR', S02NR', NR'SO2, NR'CSO, OCSNR', NR'CSNR', P(O)(OH)NR', NR'P(O)-(OH) darstellt, worin R' H, (C1-C8)Alkyl oder R3 ist,
    - R3 Alkyl, Phenyl, Alkyl, das durch eine oder mehrere Phenyl- oder Alkylenoxygruppen substituiert oder unterbrochen ist; Amino oder Amido darstellt, die durch Alkyl, das gegebenenfalls durch eine der vorangehenden Gruppen substituiert oder unterbrochen ist, substituiert oder nicht substituiert ist, wobei die Phenyl-, Phenylen- und heterocyclischen Gruppen durch OH, Cl, Br, I, (C1-C8)Alkyl, (C1-C8)Alkyloxy, NO2, NRxRy, NRxCORy, CONRxRy oder COORx substituiert sein können und Rx und Ry H oder (C1-C8)Alkyl sind und die geraden, verzweigten oder cyclischen C1- bis C14-Alkyl-, Alkylen- und Alkoxygruppen hydroxyliert sein können,
    - Ra bis Ri unabhängig H, Alkyl, Hydroxyalkyl, Alkylphenyl oder Cycloalkyl darstellen,
    - U eine Gruppe -CXR4-Verbindungsgruppe 1, CHR4CON-Verbindungsgruppe 1 oder CHR4-CHR5OH-Verbindungsgruppe 1 ist, wobei
    - R4 und R5 unabhängig H, Alkyl oder Hydroxyalkyl darstellen,
    - X die vorstehende Bedeutung aufweist,
    - Id, Ie und If die Bedeutungen:
    Figure imgb0293
     aufweisen,
    - X, R1 und Ra bis Ri dieselbe Bedeutung wie vorstehend aufweisen und
    - U' eine Verbindungsgruppe 1 ist,
    sowie die Salze der Verbindungen der Formel (E) mit pharmazeutisch annehmbaren Mineralsäuren oder -basen oder organischen Säuren oder Basen.
  2. Verbindungen gemäß Anspruch 1, wobei:
    - D ein aromatisches Gerüst, vorzugsweise des 1,3,5-Triazintyps der Formel:
    Figure imgb0294
     ist, das durch Carboxylat- und/oder Amingruppen polyfunktionalisiert ist,
    - die Verbindungsgruppe 1 und die Verbindungsgruppe 2 aus a) und b), bevorzugt a) ausgewählt sind:
    a) (CH2)2-ϕ-NH2, (CH2)3-NH2, NH-(CH2)2-NH, NH-(CH2)3-NH
    a) P1-I-P2, wobei P1 und P2 gleich oder verschieden sind und aus OH, SH, NH2, fehlt, CO2H, NCS, NCO und SO3H ausgewählt sind,
    und I = Alkylen, Alkoxyalkylen, Polyoxyalkylen, durch Phenylen, Alkyliden oder Acyliden unterbrochenes Alkylen,
    - W der Rest eines organischen Moleküls ist, das m Carbonylgruppen trägt, die mit A Carbonsäureamidgruppen bilden oder W eine Gruppe
    Figure imgb0295
     ist.
  3. Verbindungen gemäß Anspruch 1 oder 2, wobei R1 (CH2)xCONHR mit x = 1, 2 oder 3 darstellt und R eine hydrophile Gruppe mit einem Molekulargewicht über 300 ist, ausgewählt aus:
    1) einer Gruppe
    Figure imgb0296
     und Z ist eine Bindung, CH2, CH2CONH oder (CH2)2NHCO,
    Z' ist eine Bindung, O, S, NQ, CH2, CO, CONQ, NQCO, NQ-CONQ oder CONQCH2CONQ,
    Z" ist eine Bindung, CONQ, NQCO oder CONQCH2CONQ,
    p und q sind ganze Zahlen, deren Summe 0 bis 3 beträgt,
    R1, R2, R3, R4 oder R5 stellen
    - entweder unabhängig voneinander H, Br, Cl, I, CONQ1Q2 oder NQ1COQ2 dar, wobei Q1 und Q2, die gleich oder verschieden sind, H oder eine mono- oder polyhydroxylierte oder gegebenenfalls durch ein oder mehrere Sauerstoffatome unterbrochene (C1-C8)Alkylgruppe sind und mindestens eines und höchstens zwei von R1 bis R5 CONQ1Q2 oder NQ1COQ2 sind;
    - oder R2 und R4 stellen
    Figure imgb0297
     dar und R1, R'1, R3, R'3, R5 und R'5, die gleich oder verschieden sind, stellen H, Br, Cl oder I dar, Q1 und Q2 weisen dieselbe Bedeutung wie vorangehend auf und Z"' ist eine aus CONQ, CONQCH2CONQ, CONQCH2, NQCONQ, CONQ(CH2)2NQCO ausgewählte Gruppe und Q ist H oder gegebenenfalls hydroxyliertes (C1-C4)Alkyl,
    wobei die Alkylgruppen gerade oder verzweigt sein können;
    2) einer "Flash" genannten Verzweigung
    Figure imgb0298
    wobei Z"" NQCH2(CH2OCH2)i(CH2)jNH2 mit i = 2 bis 6 und j = 1 bis 6 ist.
  4. Verbindungen gemäß Anspruch 1 der Formel:

            W1-(A1)m1 (I1) PolyM RR

    worin:
    - m1 3, 4, 5 oder 6 ist,
    - W1 der Rest eines organischen Moleküls ist, das m1 Carbonylgruppen trägt, die mit A1 Carbonsäureamidgruppen bilden
    oder W1 eine Gruppe
    Figure imgb0299
     ist,
    - A1 die Gruppe
    Figure imgb0300
     darstellt, worin
    - S1-T-S2 entweder
    Figure imgb0301
     worin S1 = S2 = (CH2)2
    und B1, B2 und B3 alle drei (CH2)xCONHR mit x = 1, 2 oder 3 darstellen,
    oder
    Figure imgb0302
     mit k = 0 und S1 = S2 =CH2, wobei eines von B1, B2 und B3 G-NH darstellt und die anderen (CH2)xCONHR darstellen,
    oder
    Figure imgb0303
     mit k = 1 ist, wobei B1, B2 und B3 alle drei (CH2)xCONHR mit x = 1, 2 oder 3 darstellen und GNH aus:
    den Gruppen -(CH2)n-NH- mit n = 1 bis 4
    oder
    Figure imgb0304
     mit p = 0 bis 3 ausgewählt ist,
    wobei
    - R eine hydrophile Gruppe mit einem Molekulargewicht über 200 darstellt und R bevorzugt eine Gruppe
    Figure imgb0305
     darstellt und Z eine Bindung, CH2, CH2CONH oder (CH2)2NHCO ist
    Z' eine Bindung, O, S, NQ, CH2, CO, CONQ, NQCO, NQ-CONQ oder CONQCH2CONQ ist,
    Z" eine Bindung, CONQ, NQCO oder CONQCH2CONQ ist,
    p und q ganze Zahlen sind, deren Summe 0 bis 3 beträgt,
    R1, R2, R3, R4 oder R5
    - entweder unabhängig voneinander H, Br, Cl, I, CONQ1Q2 oder NQ1COQ2 darstellen und Q1 und Q2, die gleich oder verschieden sind, H oder eine mono- oder polyhydroxylierte oder gegebenenfalls durch ein oder mehr Sauerstoffatome unterbrochene (C1-C8)Alkylgruppe sind und mindestens eines und höchstens zwei R1 bis R5 CONQ1Q2 oder NQ1COQ2 sind,
    oder R2 und R4
    Figure imgb0306
     darstellen und R1, R'1, R3, R'3, R5 und R'5, die gleich oder verschieden sind, H, Br, Cl oder I darstellen, Q1 und Q2 dieselbe Bedeutung wie vorangehend aufweisen und Z'" eine aus CONQ, CONQCH2CONQ, CONQCH2, NQCONQ und
    CONQ(CH2)2NQCO ausgewählte Gruppe ist und Q H oder gegebenenfalls hydroxyliertes (C1-C4)Alkyl ist, wobei die Alkylgruppen gerade oder verzweigt sein können,
    oder eine FLASH-Gruppe der Formel
    Figure imgb0307
     darstellen und Z"" NQCH2(CH2OCH2)i(CH2)jNH2 ist und i = 2 bis 6 und j = 1 bis 6, sowie die Salze der Verbindungen der Formel I1 mit pharmazeutisch annehmbaren Mineralsäuren oder -basen oder organischen Säuren oder Basen.
  5. Verbindungen gemäß Anspruch 1 der Formel

            W2-(A2)m2 (12) PolyD RR,

    worin
    - m 2, 3 oder 4 ist,
    - W2 der Rest eines organischen Moleküls ist, das m2 Carbonylgruppen trägt, die mit A2 Carbonsäureamidgruppen bilden,
    oder W2 eine Gruppe
    Figure imgb0308
     ist,
    - A2 1) die Gruppe
    Figure imgb0309
     darstellt, worin
    - S1-T-S2
    Figure imgb0310
    ist, worin S1 = S2 = (CH2)2 ist und
    B1, B2 und B3 alle drei (CH2)xCONHR mit x = 1, 2 oder 3 darstellen,
    - oder A2 2)
    Figure imgb0311
     IIa2 (N-funktionalisiertes PCTA genannte Verbindung) oder
    IIb2 (N-funktionalisiertes PCTA genannte Verbindung und Stellungsisomer von IIb2) darstellt
    Figure imgb0312
    worin S1-T-S2-
    Figure imgb0313
     mit k = 0 und S1 = S2 = CH2, wobei
    bei IIa2 B3 G-NH bedeutet und B1 und B2 (CH2)xCONHR bedeuten,
    bei IIb2 B2 G-NH bedeutet und B1 und B3 (CH2)xCONHR bedeuten,
    - oder A2 3)
    Figure imgb0314
     IIc2 (C-funktionalisiertes PCTA genannte Verbindung)
    darstellt, wenn S1-T-S2-
    Figure imgb0315
     mit k = 1 und S1 = S2 =CH2 ist,
    wobei IIc2 B1, B2 und B3 alle drei (CH2)xCONHR mit x = 1, 2 oder 3 bedeuten,
    wobei bei II2, IIa2, IIb2 und IIc2
    GNH aus den Gruppen -(CH2)n-NH- mit n = 1 bis 4
    oder
    Figure imgb0316
     mit p = 0 bis 3 ausgewählt ist,
    - und D (Div - Verbindungsgruppe 2) ist und eine Trenngruppe ist, wobei Div bevorzugt vom 1,3,5-Triazintyp ist und D bevorzugt
    Figure imgb0317
     oder
    Figure imgb0318
     ist,
    - R eine hydrophile Gruppe mit einem Molekulargewicht über 200 ist und R bevorzugt eine Gruppe
    Figure imgb0319
     darstellt und Z eine Bindung, CH2, CH2CONH oder (CH2)2NHCO ist,
    Z' eine Bindung, O, S, NQ, CH2, CO, CONQ, NQCO, NQ-CONQ oder CONQCH2CONQ ist,
    Z" eine Bindung, CONQ, NQCO oder CONQCH2CONQ ist,
    p und q ganze Zahlen sind, deren Summe 0 bis 3 beträgt,
    R1, R2, R3, R4 oder R5
    - entweder unabhängig voneinander H, Br, Cl, I, CONQ1Q2 oder NQ1COQ2 darstellen und Q1 und Q2, die gleich oder verschieden sind, H oder eine mono- oder polyhydroxylierte oder gegebenenfalls durch ein oder mehr Sauerstoffatome unterbrochene (C1-C8)Alkylgruppe sind und mindestens eines und höchstens zwei R1 bis R5 CONQ1Q2 oder NQ1COQ2 sind,
    - oder R2 und R4
    Figure imgb0320
     darstellen und R1, R'1, R3, R'3, R5 und R'5, die gleich oder verschieden sind, H, Br, Cl oder I darstellen, Q1 und Q2 dieselbe Bedeutung wie vorangehend aufweisen und Z"' eine aus CONQ, CONQCH2CONQ, CONQCH2, NQCONQ und
    CONQ(CH2)2NQCO ausgewählte Gruppe ist und Q H oder gegebenenfalls hydroxyliertes (C1-C4)Alkyl ist, wobei die Alkylgruppen gerade oder verzweigt sein können,
    oder eine FLASH-Gruppe der Formel
    Figure imgb0321
     darstellen und Z"" NQCH2(CH2OCH2)i(CH2)jNH2 mit i = 2 bis 6 und j = 1 bis 6 ist, sowie die Salze der Verbindungen der Formel I1 mit pharmazeutisch annehmbaren Mineralsäuren oder -basen oder organischen Säuren oder Basen.
  6. Verbindungen gemäß einem der vorangehenden Ansprüche, bei denen W bei den Verbindungen der Formel (E), W1 bei den Verbindungen der Formel I1 beziehungsweise W2 bei den Verbindungen der Formel 12 aus den Gruppen
    Figure imgb0322
     ausgewählt ist und m gleich der Zahl der freien Bindungen von W ist.
  7. Verbindungen gemäß einem der Ansprüche 1 bis 4, bei denen W bei den Verbindungen der Formel (E), W1 bei den Verbindungen der Formel I1 beziehungsweise W2 bei den Verbindungen der Formel 12
    Figure imgb0323
     ist.
  8. Verbindungen gemäß einem der Ansprüche 1 bis 4, bei denen W bei den Verbindungen der Formel (E), W1 bei den Verbindungen der Formel I1 beziehungsweise W2 bei den Verbindungen der Formel 12
    Figure imgb0324
     oder
    Figure imgb0325
     ist.
  9. Verbindungen gemäß einem der Ansprüche 1 bis 4, bei denen W bei den Verbindungen der Formel (E), W1 bei den Verbindungen der Formel I1 beziehungsweise W2 bei den Verbindungen der Formel 12
    Figure imgb0326
     ist.
  10. Verbindungen gemäß einem der vorangehenden Ansprüche, bei denen x 2 ist.
  11. Verbindungen gemäß einem der Ansprüche 4 oder 6 bis 10 der Formel I1, worin -S1-T-S2-
    Figure imgb0327
     mit S1 = S2 = CH2 darstellt.
  12. Verbindungen gemäß Anspruch 11 der Formel I1, worin k 1 ist und G -(CH2)3- ist.
  13. Verbindungen gemäß Anspruch 11 der Formel I1, worin k 0 ist und B2 oder B3-(CH2)3NH- oder
    Figure imgb0328
     ist.
  14. Verbindungen gemäß einem der Ansprüche 4 bis 10 der Formel I1 oder 12, worin -S1-T-S2-
    Figure imgb0329
     mit S1 = S2 = (CH2)2 darstellt.
  15. Verbindungen gemäß einem der vorangehenden Ansprüche, bei denen B1, B2 und B3, wenn sie nicht -G-NH darstellen, -(CH2)2CONHR darstellen und bei R p = q = 0 und Z -CHCONH ist.
  16. Verbindungen gemäß Anspruch 15, wobei R
    Figure imgb0330
     darstellt und X gleich ist und Br oder I darstellt, während Q1 und Q2, die gleich oder verschiedenen sind, mono- oder polyhydroxylierte (C1-C8)Alkylgruppen der Art sind, daß jede Gruppe CONQ1Q2 insgesamt 4 bis 10 Hydroxy umfaßt.
  17. Verbindungen gemäß Anspruch 15, wobei R
    Figure imgb0331
     darstellt und X gleich ist und Br oder I sind, während Q1 und Q2, die gleich oder verschiedenen sind, mono- oder polyhydroxylierte (C1-C8)Alkylgruppen der Art sind, daß jede Gruppe CONQ1Q2 insgesamt 4 bis 10 Hydroxy umfaßt.
  18. Verbindungen gemäß einem der Ansprüche 1 bis 14, wobei R
    Figure imgb0332
     darstellt, Z CH2 oder CH2CONH ist, Z' CONH oder CONHCH2CONH ist, R1, R3 und R5 gleich sind und Br oder I sind und Q1 und Q2, die gleich oder verschiedenen sind, mono- oder polyhydroxylierte (C1-C8)Alkylgruppen der Art sind, daß jede Gruppe CONQ1Q2 insgesamt 4 bis 10 Hydroxy umfaßt.
  19. Verbindungen gemäß einem der Ansprüche 1 bis 14, wobei R
    Figure imgb0333
     darstellt, Z CH2CONH ist, Z' CONH, Z" CONHCH2CONH ist und R1, R3 und R5 gleich sind und Br oder I sind und Q1 und Q2, die gleich oder verschiedenen sind, mono- oder polyhydroxylierte (C1-C8)Alkylgruppen der Art sind, daß jede Gruppe CONQ1Q2 insgesamt 4 bis 10 Hydroxy umfaßt.
  20. Verbindungen gemäß einem der Ansprüche 1 bis 14, wobei R
    Figure imgb0334
     darstellt und Z"" NQ(CH2)j(CH2OCH2)i(CH2)jNH2 mit i = 2 bis 6 und j = 1 bis 6, bevorzugt
    Figure imgb0335
     oder
    Figure imgb0336
     mit t = 1, 2, 3 oder 4 und n = 2 bis 6 ist.
  21. Verbindungen gemäß einem der vorangehenden Ansprüche, wobei Q1 CH2CHOHCH2OH oder CH2(CHOH)4CH2OH darstellt und Q2 CH2(CHOH)4CH2OH darstellt.
  22. Verbindungen der Formel
    Figure imgb0337
     worin x = 1, 2 oder 3 und -S1-T'-S2-
    1)
    Figure imgb0338
     mit S1 = S2 = (CH2)2
    oder
    2)
    Figure imgb0339
     mit S1 = S2 = (CH2)2 ist und eine der Gruppen Z1 oder Z2 aus den Gruppen -(-CH2)3NH2 oder
    Figure imgb0340
     ausgewählt ist und das andere Z1 oder Z2 (CH2)xCOOH ist, in Form von Salzen mit einer alkalischen Base.
  23. Verbindungen gemäß Anspruch 22 der Formel V1, worin x = 2.
  24. Verbindung der Formel
    Figure imgb0341
     worin x = 1, 2 oder 3, in Form von Salzen mit einer alkalischen Base.
  25. Verbindungen gemäß Anspruch 24 der Formel VI, worin x = 2.
  26. Verbindung der Formel
    Figure imgb0342
     oder
    Figure imgb0343
     worin x = 1, 2 oder 3,
    D' = D-H,
    wobei D
    Figure imgb0344
     oder
    Figure imgb0345
     mit n = 2 bis 6 ist,
    wobei G-NH -(CH2)3-NH- oder
    Figure imgb0346
     ist, in Form von Salzen mit einer alkalischen Base.
  27. Kontrastmittel zur Bildgebung durch Magnetresonanz, dadurch gekennzeichnet, daß es eine Verbindung gemäß einem der Ansprüche 1 bis 21 gegebenenfalls in Verbindung mit einem pharmazeutisch annehmbaren Träger umfaßt.
  28. Kontrastmittel gemäß Anspruch 27 in Form einer injizierbaren sterilen Lösung.
  29. Kontrastmittel gemäß Anspruch 27 zur Verwendung bei der Diagnose einer Herzkreislauf-, Krebs- und Entzündungskrankheit.
  30. Verwendung eines Kontrastmittels gemäß Anspruch 27 zur Herstellung einer Zusammensetzung, die zur Diagnose einer Herzkreislauf-, Krebs- und Entzündungskrankheit bestimmt ist.
  31. Durchmusterungsverfahren bestehend aus dem Selektionieren der bei der Diagnose wirkungsvollen Verbindungen der Formel (E) gemäß Anspruch 1, wobei das Verfahren
    - die Herstellung eines polymetallischen Verbindungskandidaten der Formel (E),
    - die Verwendung des Verbindungskandidaten bei einem für eine diagnostische Indikation geeigneten Testprotokoll und
    - die Selektion von Kandidaten umfaßt, die eine spezifische Wirksamkeit von mindestens 30%, bevorzugt mindestens 50% über der des entsprechenden, nicht polymetallischen Chelats zeigen.
EP03727569A 2002-03-05 2003-03-05 Oligomere der gadolinium chelate, ihre verwendung als nmr-kontrastmittel und zwischenverbindungen Expired - Lifetime EP1480979B1 (de)

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AU2003233361A1 (en) 2003-09-16
ATE361299T1 (de) 2007-05-15
DE60313585D1 (de) 2007-06-14
AU2003233361A8 (en) 2003-09-16
EP1480979A2 (de) 2004-12-01
FR2836916B1 (fr) 2004-06-11
WO2003074523A2 (fr) 2003-09-12
US20070098643A1 (en) 2007-05-03
FR2836916A1 (fr) 2003-09-12

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